Stereospecific reduction of 3-keto steroids

ABSTRACT

The reduction of 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3one with the reducing agent produced from an alkali metal hydride and a tertiary carbinol containing at least five carbon atoms results in selective production of the 3 Beta -hydroxy epimer in excellent yield.

United States Patent lnventor Paul D. Klimstra Northbrook, Ill.

App]. No. 803,445

Filed Feb. 28, 1969 Patented Nov. 23, 1971 Assignee G. D. Searle & Co.

Chicago, Ill.

STEREOSPECIFIC REDUCTION OF 3-KETO STEROIDS 8 Claims, No Drawings US. Cl 260/3975 Int. Cl C07c 169/20 Field of Search t 260/3975 [56] References Cited UNITED STATES PATENTS 3,176,013 3/1965 Klimstra 260/239.55 FOREIGN PATENTS 6,712,308 3/1968 Netherlands Primary Examiner-Lewis Gotts Assistant Examiner-Ethel G. Love Attorneys-John M. Brown, John J. Kolano, Elliot N.

Schubert, Walter C. Ramm and Helmut A. Wegner STEREOSPECIFIC REDUCTION OF 3-KETO STEROIDS The present invention is concerned with a novel process involving the stereospecific reduction of 1701- ethynyl-l7B- hydroxyestr-4-en-3-one to afford the desired 3B-hydroxy epimer. 17a-Ethynylestr-4-ene-3B, l7B-diol, as is disclosed in US. Pat. No. 2,843,609, is a potent progestational agent and is useful also as the immediate precursor of the corresponding 3,17-diacetate, i.e. the progestin component of a commercial anti-ovulatory product.

Previous methods available for manufacture of 17aethynylestr-4-ene-3B, l7B-diol suffer from the disadvantage that a substantial quantity of the Zia-isomer is formed in the reduction. Not only is the yield thus reduced but isolation of the desired product is made much more difiicult due to the presence of that impurity. Sondheimer et al., tetrahedron, 5, (1959) Tetrahedron, thus reported that the reduction of l 7a-ethynyl- 1 7B-hydroxyestr-4-en-3-one with sodium borohydride resulted in a nonhomogeneous product which was very difficult to purify. The use of lithium aluminum hydride or lithium tri-(tertiary-butoxy) aluminum hydride to effect this reduction is also known in the art, but again a substantial proportion of the undesired epimer is fon'ned. Use of the latter reducing agents is described in British Pat. No. 776,427 and US. Pat. No. 3,176,013.

By the present invention it has been surprisingly discovered that the complex fon'ned between an alkali metal hydride and a tertiary carbinol in which at least one of the carbon chains contains two or more carbon atoms results in stereospecific reduction to afford the desired 3B-epimer. Preferred alkali metal aluminum hydrides are sodium aluminum hydride, potassium aluminum hydride and lithium aluminum hydride. The carbinols suitable for use in this process thus contain at least five carbon atoms and are exemplified by ethyl dimethyl carbinol, diethyl methyl carbinol, triethyl carbinol, isopropyl dimethyl carbinol, dimethyltertiary-butylcarbinol, tertiaryamyl dimethylcarbinol, etc. carbinols containing not more than a total of 18 carbon atoms are particularly preferred. A ratio of three moles of the carbinol to one mole of the hydride is particularly preferred.

The instant process is suitably conducted in a nonpolar inert organic solvent medium. Ethers such as diethyl ether and tetrahydrofuran are particularly suitable solvents. The process is conveniently carried out at temperatures between 0 and 30 C. A specific example of the process is the reaction of l7a-ethynyl-17/3-hydroxyestr-4 -en-3-one with lithium aluminum hydride and a 3 molar quantity of triethyl carbinol in tetrahydrofuran at a temperature between 0 and 30,-thus affording the desired 1 7a-ethynylestr-4-ene-3B,17,8-diol.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent from this disclosure to those skilled in the art. Temperatures are given in degrees Centigrade (C.) and quantities of materials in parts by weight unless otherwise noted.

EXAMPLE I To a solution of 1.15 parts of lithium aluminum hydride in 27 parts of tetrahydrofuran, under nitrogen, is added, dropwise at 0-5 with cooling and stirring over a period of about 45 minutes, a solution of 10.5 parts of triethyl carbinol in 18 parts of tetrahydrofuran. That mixture is stirred for about 10 minutes and a solution of three parts of l7a-ethynyl-l7fihydroxyestr-4-en-3-one in 67.5 parts of tetrahydrofuran is added over a period of a few minutes. Stirring is continued for about 2 hours, during which time the mixture is allowed to characterized by an 0:1 in chloroform, of 2 1 Purification of 2. parts of that crude product is effected by recrystallization from aqueous acetone, thus affording 2.25 parts of pure l7a-ethynylestr-4-ene-3BJ7B-diol, melting at 14ll43 and characterized by an [11],, in chloroform, of 27.

' EXAMPLE 2 To a solution of 2 parts of lithium aluminum hydride in 90 parts of tetrahydrofuran, at 0-5, is added, dropwise with stirring over a period of about 45 minutes, a solution of 13.9 parts of ethyl dimethyl carbinol in 22.5 parts of tetrahydrofuran. That mixture is stirred for about 30 minutes, at the end of which time a solution of 5 parts of l7a-ethynyl-l 7/3-hydroxyestr-4-en-3-one in 67.5 parts of tetrahydrofuran is added over a period of about 15 minutes. The resulting reaction mixture is stirred for about 2 hours, during which time it is allowed to warm to room temperature. The mixture is then poured carefully into a mixture of M00 parts of water, ice and 52.5 parts of acetic acid. The resulting precipitate is collected by filtration, washed with water and dried to afford 17aethynylestr-4-ene-3B, l7/3-diol, melting at about l36-138 and characterized by an M1 of -21. Recrystallization of 2.1 parts of that crude product from aqueous acetone results in 1.65 parts of l7a-ethynylestr-4-ene-3B, 17B-diol, melting at about 143-145 and characterized by [a] in chloroform of 26.

What is claimed is:

l. The process which comprises contacting l7a-ethynyll 7 B-hydroxyestr-4-en-3-one with lithium aluminum hydride and a tertiary carbinol containing at least five carbon atoms and isolating l7a-ethynylestr-4-ene-3B, 17B-diol.

2. As in claim 1, the process which comprises contacting l7a-ethynyl-17/3-hydroxyestr-4-en-3-one with lithium aluminum hydride and dimethyl ethyl carbinol and isolating 17aethynylestr-4-ene-3B, l'lfi-diol.

3. As in claim 1, the process which comprises contacting l7a-ethynyl-17B-hydroxyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol and isolating 170:-

V ethynylestr-4-ene-3B, 17B-diol.

4. As in claim 1, the process which comprises contacting l7a-ethynyl-l7B-hydroxyestr-4-en-3-one with lithium aluminum hydride and a tertiary carbinol containing at least five carbon atoms in tetrahydrofuran and isolating 17aethynylestr-4-ene-3B, l7B-diol.

5. As in claim 1, the process which comprises contacting l7a-ethynyl-l7B-hydroxyestr-4-en-3-one with lithium aluminum hydride and dimethyl ethyl carbinol in tetrahydrofuran and isolating l7a-ethynylestr-4-ene-3B, 17B-diol.

6. As in claim 1, the process which comprises contacting l7a-ethynyl-l7B-hydroxyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol in tetrahydrofuran and isolating 17a-ethynylestr-4-ene-3fi, l7B-diol.

7. As in claim 1, the process which comprises contacting l7a-ethynyl-17B-hydroxyestr-4-en-3-one with o lithium aluminum hydride and dimethyl ethyl carbinol in tetrahydrofuran at 030 and isolating l7a-ethynylestr-4-ene-3B, l7/3-diol.

8. As in claim 1, the process which comprises contacting l7a-ethynyl-17B-hydr0xyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol in tetrahydrofuran at 30 and isolating 17a-ethynylestr-4-ene-3B, l7B-diol. 

2. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and dimethyl ethyl carbinol and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol.
 3. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol and isolating 17 Alpha -ethynylestr-4-eNe-3 Beta , 17 Beta -diol.
 4. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and a tertiary carbinol containing at least five carbon atoms in tetrahydrofuran and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol.
 5. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and dimethyl ethyl carbinol in tetrahydrofuran and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol.
 6. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol in tetrahydrofuran and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol.
 7. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and dimethyl ethyl carbinol in tetrahydrofuran at 0*-30* and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol.
 8. As in claim 1, the process which comprises contacting 17 Alpha -ethynyl-17 Beta -hydroxyestr-4-en-3-one with lithium aluminum hydride and triethyl carbinol in tetrahydrofuran at 0*-30* and isolating 17 Alpha -ethynylestr-4-ene-3 Beta , 17 Beta -diol. 